Applications for this project are now closed.
Fragment-based methods are a staple of modern drug discovery, using collections of small molecules to sample a larger proportion of chemical space than is achieved by traditional high-throughput screening. The benefit of screening fragments using crystallographic methods is that it provides immediate structural information of ligand binding modes, protein conformation and how fragments can be advanced into lead-like molecules and eventually clinical drugs.
Advances in synchrotron capabilities and the introduction of streamlined crystal soaking methods using the facilities on the XChem platform at Diamond Light Source has led to substantial improvements in throughput and integration between crystal soaking, data collection and hit identification. These ongoing improvements mean that larger fragment collections can be screened and provide more opportunities for follow-up.
Although the structural information available from an XChem screen can immediately identify subtle differences in protein conformation upon ligand binding, a systematic analysis of whether the protein and fragment conformations are consistent when multiple ligands are present simultaneously, has not yet been reported. Furthermore, additional heterogeneity in binding events and protein conformation may be observed by collecting data at non-cryogenic temperatures.
The aim of the project is to develop routine protocols for soaking combinations of ligands of interest using the XChem platform at Diamond. This will have three direct applications:
1. Allow cocktailing of fragment libraries used for screening, improving the throughput of the platform and allowing larger libraries to be screened. Industrial users of the platform have expressed interest in applying this method which has not yet been explicitly explored at Diamond.
2. The identification of cooperative binding events and opportunities for fragment linking of previously identified hits which bind in different regions of a site of interest. This could offer vast improvements in the follow up process, helping identify lead-like molecules from fragments more efficiently.
3. Investigate the plasticity of binding events by comparing data collected at cryogenic and non-cryogenic temperatures. As cryogenic temperature may lock the target in one conformation, potentially biasing the design of lead like compounds, non cryogenic data may provide new insights on the binding events.
Please apply via our online application portal. The vacancy that you are applying for is the "Summer Placements 2022" listing, you will then have the opportunity to select up to three projects to apply for. This project's reference is 22005SP.
Applications are now closed with interviews scheduled for 7, 8, 9 and 10 February 2022.
If you are disabled and would like to be considered under the Guaranteed Interview Scheme, please let us know via the online application process.
Please note that this role does not meet the required skill level for a Skilled Worker visa and therefore we would be unable to sponsor individuals due to the current UK Home Office immigration rules. To be appointed to the role, candidates will need to have the right to work in the UK without sponsorship from us.
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